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Mucopolysaccharidosis (MPS I) Overview Mucopolysaccharidosis I (MPS I) Is an Inherited, Multisystem, Progressive Disorder

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Mucopolysaccharidosis (MPS I) Overview Mucopolysaccharidosis I (MPS I) Is an Inherited, Multisystem, Progressive Disorder Mucopolysaccharidosis (MPS I) Overview Mucopolysaccharidosis I (MPS I) is an inherited, multisystem, progressive disorder. It is caused by a deficiency of the lysosomal enzyme α-L-iduronidase which is responsible for catabolizing two glycoaminoglycans (GAGs), dermatan and heparan sulfate.1 Alpha-L-iduronidase is encoded by the IDUA gene. Pathogenic mutations to IDUA gene leads to a defective alpha-L-iduronidase enzyme with lesser than normal enzyme activity.2 The decrease activity of the enzyme causes dermatan and heparan sulfate to accumulate in the lysosome. Over time the build up of GAGs in the lysosomes leads to excess cellular storage and cellular dysfunction which ultimately lead to cell death and organ-specific clinical manifestations. Such clinical findings include coarse facial features, hepatomegaly, Incidence kyphosis cardiac valve abnormalities, joint contractures, and carpal tunnel.1 The symptoms range in severity and age of onset from patient to patient. • Severe MPS I occurs in approximately 1 in 100 000 newborns2,3 Severe MPS I (historically called Hurler syndrome)2: • Median age of diagnosis is 1 year3 • Severe developmental delay, regression, and severe somatic multi-organ complications become apparent after birth • Death occurs within the first 10 years of life Attenuated MPS I (historically called Hurler-Scheie and Scheie syndromes)2: • Median age of symptom onset ranges from 1.8 - 5.3 years of age • Median age of diagnosis ranges from 4 - 9.4 years of age • Mild to moderate somatic involvement • Rate of disease progression ranges from death in the second to third decade of life to a normal life span with significant disease burden Diagnosis Definitive diagnosis is established by: • α-L-iduronidase enzyme activity assay: demonstrating absence or deficiency (does not allow for differentiation between severe and attenuated)2 • IDUA gene sequencing: demonstrating two pathogenic variants intrans (one from each parent). Though identification of mutant alleles may not be required for diagnosis, sequencing the IDUA gene can provide secondary confirmation after enzymatic testing and can provide important information related to phenotype2 The following evaluations may support a diagnosis of MPS I: Inheritance Clinical Findings • Autosomal • MPS I patients often present with coarse facial features, early frequent upper-respiratory infections (including recessive disorder otitis media), inguinal or umbilical hernia,2 joint contractures, kyphosis/gibbus, dysostosis multiplex, corneal caused by clouding, and sleep disturbances3 mutations in both copies of the IDUA gene2 Laboratory Testing • Quantitative total urinary GAGs: Typically elevated in all MPS disorders, but can be normal in attenuated forms or with dilute urine samples2 • Individual GAGs (qualitative or quantitative): Elevated heparan sulfate and dermatan sulfate are characteristic of MPS I (and MPS II)2 Other • Skeletal assessment: Dysostosis multiplex, scoliosis, kyphosis, hip dysplasia, vertebral beaking, phalangeal tapering, carpal tunnel, pes cavus, and genu valgum1 • Echocardiogram/ECG: Mitral and aortic regurgitation, cardiomyopathy, arrhythmia, coronary artery disease can be seen1 • MRI/CT abdomen: hepatosplenomegaly can be seen in both severe and attenuated MPS I1 SGUSMA.MPSI.18.09.0534(1) Exp: 8/12/20 Sanofi Genzyme does not review or control the content of non-Sanofi Genzyme websites. These listings do not constitute an endorsement by Sanofi Genzyme of information provided by any other organizations. The following is a selection of laboratories offering both MPS I enzyme assay (α-L-Iduronidase) and IDUA sequencing and those offering an MPS enzyme panel. This is not Testing Options for MPS I an exhaustive list of labs that offer one or the other, or an endorsement of any one lab. Other testing options can be found atwww.concertgenetics.com or www.ncbi.nlm.nih.gov/gtr. Content is current at time of printing and tests may not be available in all states; please contact the laboratory to confirm test availability, sample shipping information, and all other logistics. Mobile Avg Lab Available Testing Sample Requirements Kits Blood Billing Contact TAT Draw Alpha-L-Iduronidase Enzyme WB: 1ml EDTA (lavender) tube; DBS card: 10 circles 7 d Blood, Inst, P: 617-580-2102 IDUA Sequencing WB: 1ml EDTA (lavender) tube; DBS card: 10 circles; Saliva; Buccal swab DBS, 15-25 d Yes Centogene Self-pay, Ins W: www.centogene.com Saliva IDUA Del/Dup WB: 1 ml EDTA (lavender) tube; DBS card: 10 circles; Saliva; Buccal swab 15 d Alpha-L-Iduronidase Enzyme WB: 5 ml EDTA (lavender) tube; DBS card: 5 circles 5-7 d P: 919-613-8400 IDUA Sequencing WB: 2-3 ml EDTA (lavender) tube; DBS card: 5 circles No 14 d No Inst Duke University W: https://testcatalog.duke.edu Qual/Quant GAGs 1 ml random urine, frozen 5-7 d Alpha-L-Iduronidase Enzyme WB: 3-5 ml sodium heparin (green) tube 7-10 d Blood, P: 855-831-7447 IDUA Sequencing WB: 2-10 ml EDTA (lavender) tube (volume varies with age); Saliva (per 4 wks DBS, No Inst, Ins, Self-pay E: [email protected] EGL Genetics Oragene kit) IDUA Del/Dup Saliva 2 wks W: www.egl-eurofins.com Qual/Quant GAGs 15-30 ml first morning urine, clean, no preservatives, frozen 7-10 d Alpha-L-Iduronidase Enzyme WB: 5-10 ml sodium heparin (green) tube; Plasma; DBS card: 3 circles 2 wks IDUA Sequencing WB: 5-7 ml EDTA (lavender) tube; DBS card: 3 circles; Saliva 3 wks Greenwood IDUA Del/Dup WB: 5-7 ml EDTA (lavender) tube Blood, 21 d Inst, P: 800-473-9411 DBS, No Self-pay, Ins (SC E: [email protected] Genetic Center MPS 10 Enzyme Panel + GAGs WB: 5-7 ml heparin (green) tube Saliva 3 wks residents only) W: www.ggc.org MPS 7 Enzyme Panel + GAGs DBS: 5 circles 3 wks Qual/Quant GAGs 3 ml random urine, frozen 14 d LabCorp Customers: Alpha-L-iduronidase Enzyme WB: 2ml EDTA (lavender) or ACD (yellow) tube (note, performed by 7 d P: 888-522-2677 (code 800102) Mayo) LabCorp/ W: www.labcorp.com Blood, Yes Inst, Ins, Self-Pay Integrated Buccal Integrated Customers: Genetics IDUA Sequencing (via Inheritest P: 800-848-4436 WB: 3-7 ml EDTA (lavender) or ACD (yellow) tube, Buccal swab 14-21 d Gene-Specific NGS 451910) E: [email protected] W: www.integratedgenetics.com WB: 2-10 ml sodium heparin (green) tube (volume varies with age); DBS Alpha-L-Iduronidase Enzyme 3 d The Lantern card: 3 circles Blood, P: 866-354-2910 Project (performed IDUA Sequencing WB: 2-10 ml EDTA (lavender) tube (volume varies with age); DBS card: 3 DBS, 3 wks Yes No charge* E: [email protected] (Incl Del/Dup) circles; Saliva (per Oragene kit) at PerkinElmer Saliva W: www.LanternProjectDx.com Genomics) WB: 2-10 ml sodium heparin (green) tube (volume varies with age); DBS MPS 7 Enzyme Panel 3 wks card: 3 circles Alpha-L-Iduronidase Enzyme WB: 2 ml EDTA (lavender) or ACD (yellow) tube; DBS card: 2 circles 8-15 d DBS Inst (ins can be P: 800-533-1710 Mayo Clinic WB: 3 ml (lavender) or ACD (yellow) tube; (in some billed in some IDUA Sequencing 14-20 d Yes E: [email protected] DBS card: 2-5 circles cases), cases, Inst acct Laboratories W: www.mayocliniclabs.com Saliva required) Qual/Quant GAGs 3 ml first morning urine, frozen 10-18 d WB: 5-10 ml ACD (yellow) (preferred), EDTA (lavender), or sodium P: 800-298-6470 Alpha-L-Iduronidase Enzyme Blood, 7 d heparin (green) tubes. Minimum of 3 ml. Yes Inst, Ins, Self-pay E: [email protected] Sema4 Saliva IDUA Sequencing (incl Del/Dup) WB: 5-10 ml ACD (yellow) AND 2 x 5-10 ml EDTA (lavender); Saliva 10-14 d W: www.sema4.com *Testing is performed at no charge; local charges may apply for sample collection, processing, or shipping. acct = account; avg TAT = average turnaround time; d = days; DBS = dried blood spot; del = deletion; dup = duplication analysis; GAGs = glycosaminoglycans; IDUA = iduronidase; incl = including; Ins = insurance; Inst = institution; min = minimum; N/A = not applicable; NGS = next generation sequencing; Qual = qualitative; Quant = quantitative; TAT = turnaround time; WB = whole blood; wks = weeks. References: 1. Arn P, et al. J Pediatr. 2009; 154:859-64 e3. 2. Clarke LA. NCBI Bookshelf, a service of the National Library of Medicine, National Institutes of Health (NIH). Available at: https://www.ncbi.nlm.nih.gov/books/NBK1162/. Accessed July 20, 2018.3. Beck M, et al. Genet in Med. 2014;16(10):759. SGUSMA.MPSI.18.09.0534(1) Exp: 8/12/20.
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